Asymmetric catalysis is the most efficient method for the generation of products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature. The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types. Synthetic asymmetric catalysts are usually composed of a metal reaction center surrounded by an organic ligand. The ligand usually is generated in high enantiomeric purity, and is the agent inducing the asymmetry. A prototypical reaction using these types of catalyst is the asymmetric hydrogenation of enamides to afford amino-acid derivatives (Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp. 1-17).
Although the preparation of enamides through Homer-Emmons Wittig chemistry is known, the preparation and use of substrates such as lactam-substituted 2-propenoic acid derivatives which possess a fully substituted nitrogen on the enamide are not known and the viability of the standard preparative sequence for the enamide is unclear. In general, the majority of enamides that have undergone asymmetric hydrogenation possess a hydrogen substituent on the nitrogen of the enamide. Thus the efficacy of asymmetric catalysts for the hydrogenation of lactam-substituted 2-propenoic acid derivatives is also unclear.
U.S. Pat. No. 4,696,943 discloses the synthesis of single enantiomer lactam-substituted propanoic acid derivatives useful as pharmaceutical agents for various conditions. However, these compounds were prepared by a cyclization reaction and not by the asymmetric hydrogenation of an enamide.
In light of the above, it would be desirable to produce single enantiomer lactam-substituted propanoic acid derivatives useful as pharmaceutical compounds.
The present invention relates to highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. The invention involves a multi-step synthesis to produce the lactam compounds. In one step of the reaction sequence, asymmetric hydrogenation of a lactam-enamide was performed to produce an intermediate that can ultimately be converted to a series of pharmaceutical compounds. The invention also contemplates the in situ synthesis of an intermediate of the multi-step synthesis, which provides economic advantages to the overall synthesis of the lactam compounds.
Additional advantages of the invention will be set forth in part in the description that follows, and in part will be apparent from the description or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The present invention may be understood more readily by reference to the following detailed description of aspects of the invention and the Examples included therein.
Before the present compositions of matter and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods or to particular formulations, and, as such, may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
The singular forms a, an, and the include plural referents unless the context clearly dictates otherwise.
Optional or optionally means that the subsequently described event or circumstances may or may not occur, and that the description included instances where said event or circumstance occurs and instances where it does not.
The term xe2x80x9calkyl groupxe2x80x9d may include straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1-C6-alkoxy, cyano, C2-C6-alkoxycarbonyl, C2-C6 alkanoyloxy, hydroxy, aryl and halogen. The terms xe2x80x9cC1-C6-alkoxy,xe2x80x9d xe2x80x9cC2-C6-alkoxycarbonyl,xe2x80x9d and xe2x80x9cC2-C6 -alkanoyloxyxe2x80x9d are used to denote radicals corresponding to the structures xe2x80x94OR, xe2x80x94CO2R, and xe2x80x94OCOR, respectively, wherein R is C1-C6-alkyl or substituted C1-C6-alkyl.
The term xe2x80x9ccycloalkylxe2x80x9d is used to denote a saturated, carbocyclic hydrocarbon. The term xe2x80x9csubstituted cycloalkylxe2x80x9d is a cycloalkyl group substituted with one or more of the groups described above.
The term xe2x80x9caryl groupxe2x80x9d may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from C1-C6-alkyl, substituted C1-C6-alkyl, C6-C10 aryl, substituted C6-C10 aryl, C1-C6-alkoxy, halogen, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino and xe2x80x94OR, SR, xe2x80x94SO2R, xe2x80x94NHSO2R and xe2x80x94NHCO2R, wherein R is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl, C1-C6-alkoxy and halogen.
The term xe2x80x9cheteroaryl groupxe2x80x9d includes a 5- or 6-membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl group may be substituted, for example, with up to three groups such as C1-C6-alkyl, C1-C6-alkoxy, substituted C1-C6-alkyl, halogen, C1-C6-alkylthio, aryl, arylthio, aryloxy, C2-C6-alkoxycarbonyl and C2-C6-alkanoylamino. The heteroaryl group also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence.
Reference will now be made in detail to the present aspects of the invention. Wherever possible, the same reference numbers and letters are used throughout the various formulas in the invention to refer to the same or like parts.
The present invention relates to the synthesis of enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. A reaction scheme that depicts a general sequence of reaction steps to produce the compounds of the invention is shown in Scheme 1. 
The first step depicted in Scheme 1 involves the reaction (i.e., condensation) between a compound having the formula I 
with glyoxylic acid, wherein R1 is hydrogen, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl, and
n is from 0 to 5,
to produce a compound having the formula II. 
The condensation reaction between lactam I and glyoxylic acid is generally conducted in a solvent. Examples of useful solvents include, but are not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. The amount of glyoxylic acid relative to the amount of compound I can vary. In one aspect, the glyoxylic acid is present in the amount from 0.8 to 2 equivalents per 1.0 equivalent of the compound having the formula I. The condensation reaction is generally run between ambient temperature and the boiling point of the lowest boiling component of the mixture.
The second step depicted in Scheme 1 involves converting compound II to a compound having the formula III 
wherein R1, R3, and R4 are, independently, a substituted or unsubstituted, branched or straight chain C1 to C20 alkyl group; a substituted or unsubstituted C3 to C8 cycloalkyl group; a substituted or unsubstituted C6 to C20 aryl group; or a substituted or unsubstituted C4 to C20 heteroaryl group, wherein R1 can also be hydrogen, and n is from 0 to 5.
The second step generally involves reacting a compound having the formula II with an alcohol comprising an alkyl alcohol, an aryl alcohol, or a heteroaryl alcohol, wherein the alkyl alcohol is substituted or unsubstituted, branched or straight chain C1 to C20 alkyl or substituted or unsubstituted C3 to C8 cycloalkyl; the aryl alcohol is substituted or unsubstituted C6 to C20 aryl; and the heteroaryl alcohol is substituted or unsubstituted C4 to C20 heteroaryl, wherein the heteroatom is oxygen, nitrogen, or sulfur. Although R3 and R4 need not be the same group, they can be derived from the same alcohol. In one aspect, the alcohol is a C1 to C5 alcohol, preferably methanol or ethanol. The amount of alcohol that is used can vary. In one aspect, the alcohol is present in the amount from 2.0 to 5.0 equivalents per 1.0 equivalent of the compound having the formula II.
In another aspect, the second step is generally conducted under dehydrating conditions using acid catalysis. For example, the use of a dehydrating agent such as a trialkyl orthoformate or the physical removal of water from the reaction mixture via an azeotropic distillation are useful in the present invention. When a dehydrating agent is used, the amount of dehydrating agent used relative to the amount of compound II is generally between 2 and 5 molar equivalents. In general, the alcohol can be used as the reaction solvent for the preparation of compound III; however, co-solvents can be used. Examples of co-solvents useful in the present invention include, but are not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like. A preferable co-solvent is toluene or xylene. The second step is generally performed at a temperature between ambient temperature and the boiling point of the lowest boiling component of the reaction mixture. In one aspect, the reaction is performed between 20xc2x0 C. and 120xc2x0 C.
The compounds produced in steps 1 and 2 can be represented by the general formula XI 
wherein R1, R3, and R4 are, independently, hydrogen, a substituted or unsubstituted, branched or straight chain C1 to C20 alkyl group; a substituted or unsubstituted C3 to C8 cycloalkyl group; a substituted or unsubstituted C6 to C20 aryl group; or substituted or unsubstituted C4 to C20 heteroaryl group, and n is from 0 to 5. In one aspect, n is 2. In another aspect, R1, R3, and R4 are hydrogen and n is 2. In a further aspect, R1 is hydrogen, R3 and R4 are methyl, and n is 2.
The third step in Scheme 1 involves converting compound III to the halogenated lactam compound having the formula IV 
wherein R1 and R3 are, independently, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl, wherein R1 can also be hydrogen, X is fluoride, chloride, bromide, or iodide, and n is from 0 to 5.
The third step generally involves reacting compound III with a phosphorous trihalide having the formula PX3, wherein X is fluoro, chloro, bromo, or iodo. In one aspect of the invention, the phosphorous trihalide is phosphorous trichloride or phosphorous tribromide. The amount of the phosphorus trihalide is generally between 0.8 and 2.0 molar equivalents based on compound III. Typically, the reaction is performed in an inert solvent including, but not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, and halogenated hydrocarbons such as dichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene, and the like. The third step is generally performed at a temperature between ambient temperature and the boiling point of the lowest boiling component of the reaction mixture for a time necessary to consume the majority of compound III. In one aspect, the reaction solvent is toluene or xylene and the reaction temperature is between 40xc2x0 C. and 80xc2x0 C.
The fourth step in Scheme 1 involves converting compound IV to a compound having the formula V 
wherein R1 and R3 are, independently, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl, wherein R1 can also be hydrogen,
R6 is substituted or unsubstituted, branched or straight chain C1 to C20 alkyl or substituted or unsubstituted C3 to C8 cycloalkyl, and
n is from 0 to 5. In one aspect, n is 2 and R1 is hydrogen. In another aspect of the invention, R3 is methyl or ethyl. In a further aspect, R6 is methyl or ethyl.
The fourth step is an Arbuzov reaction comprising reacting a compound having the formula IV with a phosphite having the formula P(OR6)3, wherein R6 is substituted or unsubstituted, branched or straight chain C1 to C20 alkyl or substituted or unsubstituted C3 to C8 cycloalkyl. In one aspect, the phosphite is trimethyl phosphite or triethyl phosphite. In another aspect of the invention, compound IV is the chloro or bromo compound (Xxe2x95x90Cl or Br). The amount of the phosphite is generally between 0.8 and 1.2 molar equivalents based on compound IV. The reaction is optionally conducted in the presence of a solvent including, but not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. The reaction is generally performed at a temperature between ambient temperature and the boiling point of the lowest boiling component of the reaction mixture for a time necessary to consume the majority of compound IV. In one aspect, the solvent is toluene or xylene and the reaction is performed between 40xc2x0 C. and 100xc2x0 C.
The fifth step in Scheme 1 involves converting compound V to a compound having the formula VI 
wherein R1, R2, and R3 are, independently, hydrogen, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl, and n is from 0 to 5. In one aspect, n is 2 and R1 is hydrogen. In another aspect, R2 and R3 are methyl. In a further aspect, R2 is methyl and R3 is ethyl.
The fifth step of the sequence is a Homer-Emmons Wittig reaction between phosphonate compound V and a n aldehyde having the formula HC(O)R2 to afford enamide VI. In one aspect of the invention, the aldehyde is acetaldehyde. The reaction generally involves the use of a base. For example, the base can be a moderately strong non-hydroxide base with a pKa of about 13 or above. Examples of non-hydroxide bases include, but are not limited to, amidine bases such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or guanidine bases such as tetramethylguanidine (TMG). The amount of base is usually between 1.0 and 2.0 molar equivalents based on compound V, and the amount of aldehyde is generally between 0.8 and 1.5 molar equivalents based compound V.
The reaction to produce compound VI is generally conducted in the presence of a solvent. Solvents useful in the reaction include, but are not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. The reaction is generally performed at a temperature between xe2x88x9280xc2x0 C. and the boiling point of the lowest boiling component of the reaction mixture for a time necessary to largely consume compound V. In one aspect of the invention, the reaction is performed in toluene or xylene at a temperature of 0xc2x0 C. to 50xc2x0 C.
The invention also contemplates producing compound VI from compound III in situ. The term xe2x80x9cin situxe2x80x9d is defined herein as performing two or more reaction sequences without isolating any of the intermediates that are produced during the reaction sequence. One aspect of the invention involves a method for producing the compound VI in situ, comprising
(a) reacting a compound having the formula III 
xe2x80x83wherein R3 and R4 are a substituted or unsubstituted, branched or straight chain C1 to C20 alkyl group; a substituted or unsubstituted C3 to C8 cycloalkyl group; a substituted or unsubstituted C6 to C20 aryl group; or substituted or unsubstituted C4 to C20 heteroaryl group, wherein R1 can also be hydrogen,
with PX3, wherein X is fluoride, chloride, bromide, or iodide, to produce a halogenated lactam;
(b) reacting the halogenated lactam produced in step (a) with a phosphite having the formula P(OR6)3, wherein R6 is substituted or unsubstituted, branched or straight chain C1 to C20 alkyl or substituted or unsubstituted C3 to C8 cycloalkyl, to produce a phosphonated lactam; and
(c) reacting the phosphonated lactam produced in step (b) with an aldehyde having the formula HC(O)R2, wherein R2 is hydrogen, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl,
in the presence of a base,
wherein steps (a), (b), and (c) are performed in situ. In this aspect of the invention, compounds IV and V are not isolated. The in situ preparation of compound VI would not have been expected due to the incompatibility of several of the reagents used in the in situ process. In addition, there is an economic advantage to combining multiple reaction steps without having to isolate each of compound that is produced.
The sixth step in Scheme 1 involves converting compound VI to a compound having the formula VII 
wherein R1, R2, and R3 are, independently, hydrogen, a substituted or unsubstituted, branched or straight chain C1 to C20 alkyl group; a substituted or unsubstituted C3 to C8 cycloalkyl group; a substituted or unsubstituted C6 to C20 aryl group; or substituted or unsubstituted C4 to C20 heteroaryl group,
n is from 0 to 5,and
the stereochemistry at carbon a is substantially R or S.
The term xe2x80x9csubstantially R or Sxe2x80x9d refers to the enantiomeric purity of the aformentioned compound, which is measured by the enantiomeric excess of this material. The enantiomeric excess (ee) is defined as the percent of one enantiomer of the mixture minus the percent of the other enantiomer. xe2x80x9cSubstantially Rxe2x80x9d indicates an ee of 90% or greater with the R enantiomer the major enantiomer, whilst xe2x80x9csubstantially Sxe2x80x9d indicates an ee of 90% or greater with the S enantiomer the major enantiomer. In one aspect of the invention, the stereochemistry at carbon a is substantially S. In another aspect of the invention, the stereochemistry at carbon a is substantially R.
In other aspects of the invention, the heteroatom of the heteroaryl group in compound VII is oxygen, sulfur, or nitrogen, and the substituent on the substituted alkyl, aryl, or heteroaryl group comprises alkyl, aryl, hydroxy, alkoxy, fluoro, chloro, bromo, iodo, nitro, cyano, or an ester; R2 and R3 are independently selected from methyl or ethyl; R1 is hydrogen, R2 is methyl, R3 is methyl or ethyl; and n is 2.
The conversion of compound VI to compound VII comprises hydrogenating compound VI with hydrogen in the presence of a catalyst comprised of a chiral ligand/metal complex to asymmetrically hydrogenate the carbon-carbon double bond of compound VI. The term xe2x80x9chydrogenatexe2x80x9d generally refers to reacting a carbon-carbon double or triple bond with hydrogen to reduce the degree of unsaturation. For example, the carbon-carbon double bond of compound VI is hydrogenated to produce a carbon-carbon single bond. Here, the degree of unsaturation has been reduced by one. Referring to Scheme 2, hydrogen can be added to side b (front side) or c (back side) of the carbon-carbon double bond of compound VII. The stereochemistry at carbon a of compound VII will be determined by which side of the carbon-carbon double bond hydrogen approaches. The term xe2x80x9casymmetrically hydrogenatingxe2x80x9d refers to the addition of hydrogen to a particular side or face (b or c) of the carbon-carbon double bond of compound VII in preference to the other side. The degree of asymmetric hydrogenation is described by the enantiomeric excess of the asymmetric hydrogenation product. 
The asymmetric hydrogenation of compound VI involves the use of a chiral ligand/metal complex. The chiral ligand/metal complex is composed of a chiral ligand and a metal, where the metal is either chemically bonded to the chiral ligand or the metal is coordinated to the chiral ligand. Any chiral ligand/metal complex known in the art can be used to asymmetrically hydrogenate compound VI. For example, the chiral ligand/metal complexes disclosed in Ohkuma et al. in Catalytic Asymmetric Synthesis, 2nd Ed, Wiley-VCH, 2000, pages 1-17, which is incorporated by reference in its entirety, are useful in the present invention.
In one aspect of the invention, the chiral ligand of the chiral ligand/metal complex comprises the substantially pure enantiomer or diastereomer of 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane; 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; 1,2-bis-2,5-dialkylphospholano(benzene); 1,2-bis-2,5-dialkylphospholano(ethane); 2,3 -bis-(diphenylphosphino)butane; or 2-diphenylphosphinomethyl-4-diphenylphophino-1-t-butoxycarbonylpyrrolidine.
In another aspect of the invention, the chiral ligand of the chiral ligand/metal complex comprises a substantially enantiomerically pure bis-phosphine compound comprising one phosphine residue having three phosphorus-carbon bonds and the other having two phosphorus-carbon bonds and one phosphorus-nitrogen bond. In one aspect of the invention, the chiral ligand of the chiral ligand/metal complex comprises a phosphine or a bis-phosphine compound and the metal of the chiral ligand/metal complex comprises rhodium, ruthenium, or iridium.
Examples of substantially enantiomerically pure bis-phosphine compounds, e.g., an enantiomeric excess of 90% or greater, include phosphinometallocenyl-aminophosphines having the general formulas IX and X (the enantiomer of IX): 
where R7,R8, R9, R10, R11, and R12 are, independently, hydrogen, substituted or unsubstituted branched or straight chain C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C6 to C20 aryl, and substituted or unsubstituted C4 to C20 heteroaryl, where the heteroatoms are chosen from sulfur, nitrogen, or oxygen, provided R12 is not hydrogen;
a is from 0 and 3;
b is from 0 and 5; and
M is a Group IV to Group VIII metal. The synthesis of the chiral ligands having the formulas IX and X is disclosed in U.S. Provisional Application Nos. 60/236,564 and 60/264,411, both of which are incorporated by reference in their entireties.
The alkyl groups that may be represented by each of R7, R8, R9, R10, R11, and R12 in formulas IX and X may be straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1-C6-alkoxy, cyano, C2-C6-alkoxycarbonyl, C2-C6 alkanoyloxy, hydroxy, aryl and halogen. The terms xe2x80x9cC1-C6-alkoxy,xe2x80x9d xe2x80x9cC2-C6-alkoxycarbonyl,xe2x80x9d and xe2x80x9cC2-C6-alkanoyloxyxe2x80x9d are used to denote radicals corresponding to the structures xe2x80x94OR13, xe2x80x94CO2R13, and xe2x80x94OCOR13, respectively, wherein R13 is C1-C6-alkyl or substituted C1-C6-alkyl. The term xe2x80x9cC3-C8-cycloalkylxe2x80x9d is used to denote a saturated, carbocyclic hydrocarbon radical having three to eight carbon atoms.
The aryl groups for each of R7, R8, R9, R10, R11, and R12 in formulas IX and X may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from C1-C6-alkyl, substituted C1-C6-alkyl, C6-C10 aryl, substituted C6-C10 aryl, C1-C6-alkoxy, halogen, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino and xe2x80x94Oxe2x80x94R 4, Sxe2x80x94R14,xe2x80x94SO2xe2x80x94R14, xe2x80x94NHSO2R14 and xe2x80x94NHCO2R14, wherein R14 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl, C1-C6-alkoxy and halogen.
The heteroaryl radicals include a 5- or 6-membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl radicals may be substituted, for example, with up to three groups such as C1-C6-alkyl, C1-C6-alkoxy, substituted C1-C6-alkyl, halogen, C1-C6-alkylthio, aryl, arylthio, aryloxy, C2-C6-alkoxycarbonyl and C2-C6-alkanoylamino. The heteroaryl radicals also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence. The term xe2x80x9chalogenxe2x80x9d is used to include fluorine, chlorine, bromine, and iodine.
In one aspect of the invention, when the chiral ligand is a compound having the formula IX or X, R12 is C1 to C6 alkyl (e.g., methyl); R7 is hydrogen or C1 to C6 alkyl (e.g., methyl); R8 is aryl (e.g., phenyl), ethyl, isopropyl, or cyclohexyl; R9 is aryl (e.g., phenyl); R10 and R11 are hydrogen; and M is iron, ruthenium, or osmium.
The chiral ligand/metal complex can be prepared and isolated, or, in the alternative, it can be prepared in situ. The preparation of chiral ligand/metal complexes is generally known in the art. The chiral ligand to metal molar ratio can be from 0.5:1 to 5:1, preferably from 1:1 to 1.5:1. The amount of chiral ligand/metal complex may vary between 0.0005 and 0.5 equivalents based on compound VI, with more catalyst leading to a faster reaction.
The hydrogenation reaction is conducted under an atmosphere of hydrogen, but other materials that are inert to the reaction conditions may also be present. The reaction can be run at atmospheric pressure or at elevated pressure of from 0.5 to 200 atmospheres. The reaction temperature can be varied to modify the rate of conversion, usually between ambient temperature and the boiling point (or apparent boiling point at elevated pressure) of the lowest boiling component of the reaction mixture. In one aspect of the invention, the hydrogenation step is conducted at from xe2x88x9220xc2x0 C. to 100xc2x0 C. The reaction is usually run in the presence of a solvent. Examples of useful solvents include, but are not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, dialkyl ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like.
Compounds having the formula VII can be converted to the amide compounds VIII 
wherein R1 and R2 are, independently, hydrogen, substituted or unsubstituted, branched or straight chain C1 to C20 alkyl; substituted or unsubstituted C3 to C8 cycloalkyl; substituted or unsubstituted C6 to C20 aryl; or substituted or unsubstituted C4 to C20 heteroaryl,
n is from 0 to 5, and
the stereochemistry at carbon a is substantially R or S,
comprising reacting a compound having the formula VII with NH4OH.
The amount of NH4OH can vary, wherein from 1 to 10 equivalents of NH4OH per 1.0 equivalent of the compound having the formula VII can be used. The reaction is generally performed in water optionally in the presence of a water-miscible organic solvent, including, but not limited to, a lower alcohol such as methanol or ethanol, THF, DMF, or DMSO. The reaction is preferably performed in water as the sole solvent. The reaction temperature can also vary, however; the reaction is typically performed from 0xc2x0 C. to 50xc2x0 C. The compounds having the formula VIII can be used to treat a number of different maladies, some of which are disclosed in U.S. Pat. No. 4,696,943, which is incorporated by reference in its entirety.
In summary, the invention provides lactam-substituted propanoic acid derivatives that are useful precursors to enantiomerically-pure lactam-substituted propanoic acid derivatives. The invention provides an efficient method for making the lactam-substituted propanoic acid derivatives as well as the enantiomerically enriched compounds, which will ultimately be used to produce pharmaceutical compounds.
Throughout this application, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.